The invention concerns a method for the production of 1-alkyl-6,7-methylenedioxy-4(1H)-oxo-cinnolin-3-carboxylic acids of the general Formula V ##STR1## which are used as highly effective chemotherapeutics, particularly for the treatment of urinary tract infections.
The production of 1-alkyl-6,7-methylenedioxy-4(1H)-oxo-cinnolin-3-carboxylic acids is previously known only from DE-OS No. 2,005,104 corresponding to U.S. applications Ser. Nos. 796,546 and 888,880 and DE-OS No. 2,065,719. Accordingly, 4,5-methylene-dioxy-2-amino-acetophenone is converted, through diazotization and heating, into 6,7-methylenedioxy-4(1H)-oxo-cinnolin, and through four further stages, bromination in the 3-position, exchange of bromine by cyano by means of CuCN, alkylation of the nitrile in the 1-position with alkyl halogenide and NaH, and subsequent saponification of the nitrile, made into carboxylic acid. The process possesses the disadvantage that proceeding from the 4,5-methylenedioxy-2-amino-acetophenone, the final compound is produced through five relatively expensive stages. On account of the extraordinarily great insolubility of the obtained intermediate compounds, the process must be performed at high temperatures using high-boiling solvents such as acetic acid and dimethylformamide.
Another method for the production of 6,7-methylenedioxy-4(1H)-oxo-cinnolin-3-carboxylic acid unsubstituted by nitrogen proceeds from o-nitropiperonal, which is condensed into the corresponding cinnamic acid derivative through condensation with malonic acid diethylester. Through bromination and subsequent HBr-splitting-off into o-nitropropiolic acid, reduction to amino group with subsequent diazotization and ring closure, the 6,7-methylenedioxy-4(1H)-oxo-cinnolin-3-carboxylic acid is obtained (J. Chem. Soc. 1945 512; 1949 2393). This synthesis is expensive and produces very low yields on account of the numerous side reactions, in particular with the cyclization of the diazotized o-aminopropiolic acid, and is therefore practically not utilized (T. L. Jacobs in Elderfield, Heterocyclic Compounds, 1977, Chapter 5, page 137).
4(1H)-oxo-cinnolin-3-carboxylic acid derivatives can moreover be produced through the corresponding phenylhydrazones of mesoxalic acid dichloride through cyclization with suitable Friedel-Crafts catalysts. The mesoxalic acid dichloride-phenylhydrazone is prepared from the corresponding aniline through diazotization and coupling with malonic acid ester, subsequent saponification of the mesoxalic acid diester-phenylhydrazone into the dicarboxylic acid and reaction with phosphorpentachloride or thionylchloride (H. J. Barber et al., J. Chem. Soc. 1961 2828, U.S. Pat. No. 2,797,218 of Aug. 2, 1954). As suitable catalysts particularly TiCl.sub.4 and SnCl.sub.4 are mentioned. Various substituents in the aromatic ring, in particular alkoxy groups, are, however, attacked through the catalysts, so that low yields are obtained or exclusively resinified products are produced.
The production of the acid chloride serving as starting product for the cyclization is unfavorable, on account of the aggressiveness of the reactants, and leads to a higher technical expenditure.
The solution of the problem according to the present invention was not foreseen; the attempts by Barber and collaborators to obtain a cyclization at the stage of the mesoxalic acid ester or mesoxalic acid-phenylhydrazone with catalysts such as TiCl.sub.4, SnCl.sub.4, POCl.sub.3 or polyphosphoric acid, did not succeed (J. Chem. Soc. 1961 2828). Moreover, the N-alkylation of the 4(1H)-oxo-cinnolin-3-carboxylic acid with alkyl halogenide under basic conditions leads to mixtures of approximately the same portions of N.sub.1 and N.sub.2 -substituted compounds, which, such as with the described 6-bromo-4(1H)-oxo-cinnolin-3-carboxylic acid, can be separated only with difficulty (D. E. Ames et al., J. Chem. Soc. 1964 5659; R. P. Brundage et al., J. Heteroc. Chem. 13 1085 (1976)).